Method of treating disorders of the eye

ABSTRACT

The present invention relates, in general, to methods of treating disorders of the eye, and, in particular, to methods of preventing or treating elevated eye pressure and glaucoma. The invention further relates to compounds and compositions suitable for use in such methods.

This is a divisional of application Ser. No. 08/180,482, field Jan. 12,1994 now U.S. Pat. No. 5,458,883.

This invention was made, at least in part, with support from theNational Eye Institute of the National Institutes of Health (Grant No.EY01894). The Government has certain rights in the invention.

TECHNICAL FIELD

The present invention relates, in general, to methods of treatingdisorders of the eye, and, in particular, to methods of treatingdiseases characterized by elevated intraocular pressure (ocularhypertension), such as glaucoma. The invention further relates tocompounds and compositions suitable for use in such methods.

BACKGROUND

Glaucoma is a disease of the eye that is characterized by an elevationin intraocular pressure. The elevation in pressure results from animpairment in the outflow of aqueous humor from the anterior chamber ofthe eye via the trabecular meshwork (see Tripathi et al, Drug Develop.Res. 27:191 (1992)). Treatments for glaucoma focus on decreasingintraocular pressure and thereby avoiding damage to the optic nerve.Left untreated, glaucoma can lead to blindness.

Numerous agents have been used for the treatment of glaucoma, however,many are accompanied by undesirable side effects, such as ocular painand localized allergy. Examples of such agents include adrenergic amine,epinephrine, and cholinesterase inhibitors. Although topical applicationis typically used, absorption of at least certain of these compounds canresult in adverse systemic effects including headaches, nausea and thelike.

U.S. Pat. No. 4,757,089 discloses a treatment for glaucoma that involvesthe administration to the eye of ethacrynic acid or analogs thereof thatreact with sulfhydryl groups of the trabecular meshwork of the eye.Erickson-Lamy et al (Invest. Opthalmol. Vis. Sci. 33:2631 (1992)) havereported that ethacrynic acid, acting via a SH-reactive mechanism,induces cytoskeletal changes that result in the observed physiologiceffects on outflow facility. WO 92/16199 discloses an improvement in themethod described in U.S. Pat. No. 4,757,089 that involves the use ofagents that mask the sulfhydryl reactive site as the drug passes intothe eye. The masking agent dissociates in the eye thereby freeing thesulfhydryl reactive site for interaction with the trabecular meshwork.Use of such masking agents prevents side effects (such as corneal edema)that occur in the absence of the masks. (See also Epstein et al, CurrentEye Res. 11:253 (1992).)

The present invention provides a further approach to glaucoma treatment.The present method involves the use of compounds that increase aqueoushumor outflow but are non-SH reactive. The mechanism of action of thepresent compounds would thus appear to be distinct from that ofethacrynic acid and the analogs thereof disclosed in U.S. Pat. No.4,757,089 and WO 92/16199.

OBJECTS AND SUMMARY OF THE INVENTION

It is a general object of the invention to provide a method of treatingdisorders of the eye.

It is a specific object of the invention to provide a method of treatingglaucoma, or elevated eye pressure, by increasing aqueous humor outflow.

It is another object of the invention to provide a method of preventingthe onset of glaucoma, for example, following cataract surgery.

It is a further object of the invention to provide compounds andcompositions suitable for use in preventing or treating glaucoma, orelevated eye pressure, and to provide container means that include same.

In one embodiment, the present invention relates to a method of loweringintraocular pressure in an eye of a warm-blooded animal in need of suchtreatment. The method comprises administering to the eye anon-sulfhydryl reactive derivative of phenoxyacetic acid capable ofincreasing aqueous humor outflow in an amount sufficient to effect thetreatment.

In another embodiment, the present invention relates to a method ofpreventing the onset of glaucoma in an eye of a warm-blooded animal inneed of such prevention. The method comprises administering to the eye anon-sulfhydryl reactive derivative of phenoxyacetic acid capable ofincreasing aqueous humor outflow in an amount sufficient to effect theprevention.

In a further embodiment, the present invention relates to apharmaceutical composition comprising a non-sulhydryl reactivederivative of phenoxyacetic acid and a pharmaceutically acceptablecarrier, wherein said composition is in the form of an ointment, creamor gel.

In yet another embodiment, the present invention relates to a containerhaving disposed therewithin a solution of a non-sulfhydryl reactivederivative of phenoxyacetic acid that increases aqueous humor outflow,wherein the container includes an outlet means suitable for dispensingthe solution from the container in droplets.

Further objects and advantages of the present invention will be clearfrom the description that follows.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to methods of preventing and treatingdisorders of the eye characterized by elevated intraocular pressure,particularly, glaucoma. The present method results in an increase inaqueous humor outflow and thus a reduction in intraocular pressure thatcan be deleterious to the optic nerve.

Compounds suitable for use in the present method include non-SH-reactivephenoxyacetic acid derivatives, such as the anti-hypertensive agentsindacrinone and ticrynafen, as well as non-SH-reactive derivativesthereof that increase aqueous humor outflow. The non-SH reactivity canbe assessed, as described in the Examples below, by administering thecompounds in combination with cysteine. Cysteine, which contains areactive sulfhydryl group, has been shown in prior studies to beineffective in influencing aqueous humor outflow. When administered incombination with ethacrynic acid, however, cysteine blocks the abilityof that compound to increase outflow facility, thus indicating thatethacrynic acid exerts its effects by a sulfhydryl related mechanism(see U.S. Pat. No. 4,757,089). (See also Epstein et al, Current Eye Res.11:253 (1992) and Tingey et al, Arch. Ophthal. 110:699 (1992)). Cysteineused in combination with non-sulfhydryl reactive phenoxyacetic acidderivatives does not block the ability of these compounds to increaseoutflow facility (see Examples).

Compounds suitable for use in the invention have a margin of safety ofat least 2.0 and, advantageously, at least 4.0. That margin is measuredas the ratio of the dosage of an aqueous humor outflow increasingcompound that produces unacceptable side effects and the dosage thatproduces a clinically significant increase in aqueous humor outflow in apatient suffering advanced open angle glaucoma. Compounds suitable foruse in the present method do not produce permanent or long termdeleterious alterations in the eye.

The compounds of the invention can be formulated into compositionssuitable for topical administration. Such compositions typically takethe form of aqueous solutions that are administered dropwise to the eye.Alternatively, the compounds can be formulated into gels, ointments orcreams that can be applied topically to the tissue surrounding the eye.The compounds of the invention can also be formulated into sterilesolutions for administration by intracameral injection into the anteriorchamber of the eye, for example, at the time of cataract surgery inorder to avoid the postoperative onset of glaucoma. Administration bydirect injection into the trabecular meshwork of the eye can also beeffective (by way of example, see Melamed et al, Am. J. Ophthal. 113:508(1992)). The compounds of the invention can also be administered to theeye by iontophoresis (see, for example, Grossman and Lee, Ophthalmology96:724 (1989); Sarraf et al, Amer. J. Ophthal. 115:748 (1993); Sarraf etal, Invest. Ophthalmol. Vis. Sci. 34 (ARVO Suppl):1491 (1993)). Systemicadministration of the compounds of the invention is also contemplated,either oral administration or intravenous administration. In the case oforal administration, a suitable composition is in dosage unit form andis a pill, capsule, tablet or the like. Compositions suitable forintravenous administration are typically formulated as sterilesolutions.

Whatever the mode of administration, the compositions of the inventioninclude, as active agent, the non-SH-reactive phenoxyacetic acidderivative, and a pharmaceutically acceptable carrier. The compositionsof the invention can also include agents that promote or enhancedelivery, such as surfactants and wetting agents, benzalkonium being onesuch agent. The compositions can also include preservatives that prolongshelf life.

The amount of active agent to be included in the composition will varywith the phenoxyacetic acid derivative, with the dosage regimen used andwith the effect sought. Preferred concentrations can be readilydetermined. Likewise, the optimum amount of phenoxyacetic acidderivative to be administered to any particular patient can bedetermined without undue experimentation.

The compounds and compositions of the invention can be provided invarious container means. Compositions to be administered topically canbe provided as sterile solutions in a container means that facilitatesadministration of the solution to the eye in drops. For example, thecontainer means can include an outlet that allows for the dispensing ofdrops directly or, alternatively, the container means can include aseparate dropper means reversibly associated therewith. Compositions tobe administered topically that are formulated as creams, gels orointments can be provided in container means that facilitateadministration to the eye or surrounding tissue. Compositions to beadministered by injection, intravenously or into the eye or surroundingtissue, can be provided as solutions in sterile container means.

The compounds and compositions of the invention are suitable for use inany mammal suffering glaucoma. While human treatment is the focus of theinvention, veterinary use is also contemplated.

Certain aspects of the invention are described in greater detail in thenon-limiting Examples that follow. Techniques used in the Examples aredescribed in one or more of Erickson-Lamy et al, Invest. Ophthal. Vis.Sci. 33:2631 (1992), Epstein et al, Invest. Ophthal. Vis. Sci. 22:752(1982), and Epstein et al Invest. Ophthal. Vis. Sci. 20:625 (1981).Prior studies with ethacrynic acid have demonstrated that the resultsobtained using the bovine eye model referenced in these publications(and in the Examples below) are predictive of comparable effects in vivo(eg in monkeys).

EXAMPLES

The experimental protocols that follow are utilized in the specificExamples set forth below:

Enucleated cow eyes were obtained from a local commercial abattoir,immediately chilled, and then perfused within twenty-four hours using astandard constant pressure perfusion technique. Pairs of eyes from asingle animal were used for each experiment and subjected to the samemanipulation except for the experimental drug in the experimental eye ofperfusion. Briefly, a 5 mm central cornea trephine button was removedfrom each eye. Radial iridotomy was performed to prevent artificialdeepening of the anterior chamber during perfusion. The anterior chamberwas then gently irrigated with perfusion medium to remove pigment whichmight have been liberated by the iridotomy. A Grant stainless steelfitting was then placed into the cornea and connected by twenty-threegauge polyethylene tubing to the fluid reservoir of the perfusionapparatus.

The perfusion medium was Dulbecco's phosphate-buffered salt solution(PBS) (Grand Island Biological Company, Grand Island, N.Y.) with added5.5 mM glucose. All solutions were filtered through a 0.2 μm Nucleporefilter.

The initial flow value was determined after the eyes had been perfusedfor one hour which allowed sufficient time to achieve adequatestability. The corneal fitting was removed, and the anterior chamber wasgently emptied and refilled with fresh perfusion medium with added drugor sham solution. The corneal fitting was replaced and the eye wasperfused for an additional five hours. The outflow facility(flow/pressure) was calculated at the end of the experiment and comparedto the initial baseline after the initial hour (pre-drug, both eyesreceived control perfusion medium for the first hour). The change in theexperimental eye was compared to the change in the fellow control eye bya paired T-test. Control eyes were treated similarly except that anosmotically equivalent amount of sodium chloride was added to theperfusion medium in place of the drug. All perfusions were performed at22° centigrade and the perfusion pressure was 15 mm of mercury.

EXAMPLE I Treatment of Bovine Eyes with Indacrinone

Ten pairs of enucleated cow eyes were perfused with 0.125 mM indacrinoneversus sham control. The baseline outflow facilities (microliters perminute per millimeter mercury pressure) were 2.35±0.20 (SEM) in thecontrol eye versus 2.21±0.19 in the experimental indacrinone eye. At theend of the experiment, outflow facility had increased 43%±6% in thecontrol eye, versus 113%±24% in the indacrinone treated eye. This wasstatistically significant at p<0.01.

In a separate set of experiments, six pairs of cow eyes were perfusedwith 0.125 mM indacrinone plus 0.625 mM cysteine (Sigma ChemicalCompany, St. Louis, Mo.) versus sham-manipulated control. The controlcontained an osmotically equivalent amount of sodium chloride. In thesesix pairs of eyes, outflow facility was 2.25±0.09 in the control eyesand 2.42±0.23 in the experimental indacrinone/cysteine treated eyes. Atthe end of the experiment, outflow facility had increased 52%±7 in thecontrol eye and 91%±8 in the experimental indacrinone/cysteine eyes. Thepaired T-test indicated that this was highly significant increase inoutflow facility with a p value of less than 0.005.

EXAMPLE II Treatment of Bovine Eyes with Ticrynafen

Six pairs of cow eyes were perfused with 0.125 mM ticrynafen versussham. Baseline outflow facility was 2.28±0.24 in the control eyes and1.87±0.41 in the experimental ticrynafen eyes. At the end of theperfusion period, outflow facility had increases 50%±20% in the controleyes and 102%±23% in the experimental ticrynafen treated eyes. The pvalue indicated a significance at less than 0.025.

In a separate experiment, six additional pairs of cow eyes were perfusedwith 0.125 mM ticrynafen with added 0.625 mM cysteine versus sham(sodium chloride added) treated eyes. The control eyes outflow facilitywas 3.12±0.18 and the experimental outflow facility was 3.19±0.11. Atthe end of the perfusion period, the control eyes had increased 32%±11%whereas the 0.125 mM ticrynafen/0.625 mM cysteine eyes had increased80%±9%. This was highly significant with a p value less than 0.01,indicating a facility increase with this combination.

All documents cited above are hereby incorporated in their entirety byreference.

One skilled in the art will appreciate from a reading of this disclosurethat various changes in form and detail can be made without departingfrom the true scope of the invention.

What is claimed is:
 1. A pharmaceutical composition consistingessentially of:ticrynafen or indacrinone in an amount effective to lowerinterocular pressure, and a pharmaceutically acceptable carrier, whereinsaid composition is in the form of an eye cream, eye gel or eyeointment.
 2. The composition according to claim 1 wherein saidcomposition consists essentially of ticrynafen and a pharmaceuticallyacceptable carrier.
 3. The composition according to claim 1 wherein saidcomposition consists essentially of indacrinone and a pharmaceuticallyacceptable carrier.
 4. A pharmaceutical composition consistingof:ticrynafen or indacrinone in an amount sufficient to lowerinterocular pressure, and a pharmaceutically acceptable carrier, whereinsaid composition is in the form of an eye cream, eye gel or eyeointment.
 5. The composition according to claim 4 wherein saidcomposition consists of ticrynafen and a pharmaceutically acceptablecarrier.
 6. The composition according to claim 4 wherein saidcomposition consists of indacrinone and a pharmaceutically acceptablecarrier.